Tetrahydrobenzothiophene compound

Abstract

A compound has an intestinal phosphate transporter (NPT-IIb) inhibitory action and is useful as an active ingredient of an agent for treating hyperphosphatemia, preventing hyperphosphatemia, or both. The compound is a tetrahydrobenzothiophene compound. A pharmaceutical composition for treating hyperphosphatemia includes the compound or salt thereof. A method of treating hyperphosphatemia includes administering to a subject an effective amount of the compound or salt thereof.

1 . A compound of formula (I) or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 1  is —O—C 1-6 , —C 1-6 -phenyl, or —C 1-6  pyridyl, with phenyl or pyridyl optionally substituted by carboxy or protected carboxy, 
         R 2  and R 3  are each independently H, C 1-6 , cycloalkyl, aryl, heteroaryl, a nitrogen-comprising saturated hetero ring, —C 1-6 -aryl, or —C 1-6  heteroaryl optionally substituted by C 1-6 , cycloalkyl, aryl, heteroaryl, or a nitrogen-comprising saturated hetero ring, or R 2  and R 3  are combined with a nitrogen atom to which they bind to form an optionally substituted 5- to 7-membered saturated cyclic amino, 
         each R 4  is independently halogen, C 1-6 , —OH, —O—C 1-6 , —NO 2 , or a group of formula (II): 
       
       
         
           
           
               
               
           
         
         R 41  and R 42  are each independently H or optionally substituted C 1-6 , or R 41  and R 42  are combined with a nitrogen atom to which they bind to form a 5- to 7-membered saturated cyclic amino, 
         n is 0 to 2, and 
         the compound of formula (I) is not N-(4-methoxyphenyl)-2-({3-[(4-methylpiperazin-1-yl)sulfonyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide. 
       
     
     
         2 - 4 . (canceled) 
     
     
         5 . The compound or salt thereof of  claim 1 , wherein n is 0. 
     
     
         6 . The compound or salt thereof according to  claim 5 ,
 wherein R 1  is —C 1-6 -phenyl and the —C 1-6 -phenyl is substituted with carboxy or protected carboxy.   
     
     
         7 . The compound or salt thereof according to  claim 6 ,
 the —C 1-6 -phenyl is substituted with carboxy.   
     
     
         8 . The compound or salt thereof according to  claim 7 , wherein R 2  is C 1-6 , cycloalkyl, or phenyl, in any case substituted by carboxy. 
     
     
         9 . The compound or salt thereof according to  claim 8 , wherein R 3  is C 1-6  or cycloalkyl. 
     
     
         10 . The compound or salt thereof according to  claim 7 , wherein R 2  and R 3  are combined with a nitrogen atom to which they bind to form optionally substituted pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, or azepan-1-yl. 
     
     
         11 . The compound or salt thereof according to  claim 10 , wherein R 2  and R 3  are combined with a nitrogen atom to which they bind to form optionally substituted piperazin-1-yl. 
     
     
         12 . The compound or salt thereof according to  claim 1 , wherein the compound or salt thereof is:
 4-{2-[4-({[2-({3-[(4-Carboxycyclohexyl)(ethyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiphen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid,   4-{2-[4-({[2-({3-[(4-carboxycyclohexyl)(cyclopropyl)sulfamoyl]benzoyl}amino)-4, 5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid,   4-{2-[4-({[2-({3-[(3-carboxypropyl)(cyclopropyl) sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid,   4-{2-[4-({[2-({3-[(1-carboxycyclopropyl)(ethyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid,   4-{2-[4-({[2-({3-[(1-carboxycyclopropyl)(isopropyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid,   4-{[(3-{[3-({4-[2-(4-carboxyphenyl)ethyl]phenyl}carbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]carbamoyl}phenyl)sulfonyl](ethyl)amino}benzoic acid,   4-{3-[4-({[2-({3-[(4-carboxycyclohexyl)(ethyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]propyl}benzoic acid,   4-{2-[4-({[2-({3-[(4-acetylpiperazin-1-yl)sulfonyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid,   4-{2-[4-({[2-({3-[(4-carboxybutyl)(cyclopropyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid,   4-{3-[4-({[2-({3-[(4-carboxycyclohexyl)(propyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]propyl}benzoic acid, or   a salt thereof.   
     
     
         13 . A pharmaceutical composition, comprising:
 the compound or salt thereof according to  claim 1 , and   a pharmaceutically acceptable excipient.   
     
     
         14 . The pharmaceutical composition according to  claim 13 , wherein the pharmaceutical composition is suitable for prevention or treatment of hyperphosphatemia. 
     
     
         15 . A method of preparing a pharmaceutical composition, comprising:
 preparing the pharmaceutical composition with the compound or salt thereof of  claim 1 ,   wherein the pharmaceutical composition is suitable for preventing or treating hyperphosphatemia.   
     
     
         16 . (canceled) 
     
     
         17 . The compound or salt thereof according to  claim 1 , wherein the compound is suitable for prevention or treatment of hyperphosphatemia. 
     
     
         18 . A method for preventing or treating hyperphosphatemia, comprising:
 administering to a subject in need thereof an effective amount of the compound or salt thereof according to  claim 1 .   
     
     
         19 . The method of  claim 18 , wherein the effective amount is a daily dose of from about 0.001 to 100 mg/kg.